The present invention relates to the prevention or treatment of pain by administering an endothelin antagonist to a subject in need thereof.
Endothelin-1 (ET-1) is a polypeptide with very potent vasoconstrictor activity. Elevated levels ET-1 are found in a variety of diseases including advanced prostate cancer and localized prostate cancer. It has been discovered that ET-1 not only functions as a vasoconstrictor but that it also has other functions, serving, for instance, as a growth factor alone or in combination with other hormones and peptides, as in prostate cancer (see, e.g., Nature Med. 1, 944-949, (1995)). In addition, as disclosed in WO 98/46076, ET-1 is related to the sorafotoxins, which are painful and lethal moieties in the venom of certain snakes of the genus Atractapsis. Similar to venom in a snake bite, recombinant ET-1 has been reported to produce intense pain in humans after the localized injection of high concentrations. Thus, for instance, in prostate cancer, a high localized concentration of ET-1 produced by the cancer cells is likely to be a major contributor to the high degree of pain associated with the late stage of the disease. Accordingly, molecules that prevent or inhibit the production of ET-1 can be expected to be useful to prevent and treat pain associated with elevated levels of endothelin.
Endothelin antagonists, which are compounds capable, inter alia, of inhibiting the binding of endothelin peptides to endothelin receptors, are useful in the treatment of endothelin-related disorders. While certain such compounds have been described as having utility in the treatment of hypertension, the present invention provides a method employing these compounds specifically for the treatment of pain.